A metal-free oxidative esterification of the benzyl C-H bond

Article abstract of DOI:10.1002/adsc.201100920

An efficient metal-free oxidative esterification of benzyl C-H bonds was developed. Using tetrabutylammonium iodide as catalyst and tert-butyl hydroperoxide as co-oxidant, benzylic substrates could react smoothly with various carboxylic acids to give the esters with good to excellent yields. The method was also suitable for the O-protection of N-Boc amino acids. The reaction mechanism was primarily investigated and a radical process was proposed. Copyright

Full text of DOI:10.1002/adsc.201100920

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DOI: 10.1002/adsc.201100920
À
A Metal-Free Oxidative Esterification of the Benzyl C H Bond
Jie Feng,a Shuai Liang,a Shan-Yong Chen,a Ji Zhang,a,* Song-Sen Fu,a
and Xiao-Qi Yua,*
a
Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8541-5886; e-mail: jzhang@scu.edu.cn or xqyu@scu.edu.cn
Received: November 25, 2011; Revised: January 19, 2012; Published online: April 26, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100930.
À
Abstract: An efficient metal-free oxidative esterifi-
cation of benzyl C H bonds was developed. Using
considerable developments in C H activation during
the last few years,[4] a new method of esterification
has been studied widely: esters were synthesized
À
tetrabutylammonium iodide as catalyst and tert-
butyl hydroperoxide as co-oxidant, benzylic sub-
strates could react smoothly with various carboxylic
acids to give the esters with good to excellent
yields. The method was also suitable for the O-pro-
tection of N-Boc amino acids. The reaction mecha-
nism was primarily investigated and a radical pro-
cess was proposed.
through oxidative coupling reactions from common
C H substrates which served as starting materials.
[5]
À
Several types of transition metals, including palladi-
AHCTUNGTRENNUNG
um,[5a–e] copper,[5f] rhodium[5g] and platinum[5h] exhibit-
À
ed excellent catalytic activity in this new C H activat-
ing esterification (Scheme 1, equation b). However,
some drawbacks such as toxicity, sensitivity to the en-
vironment, and being hard to handle after reactions,
are associated with the usage of metal catalysts.
Therefore, increasing interest has been focused on
metal-free catalysts.
À
Keywords: benzyl C H bond; esterification; metal-
free catalyst; protected amino acids; tetrabutylam-
monium iodide
In 2010, Ishihara and co-workers reported a new
class of metal-free catalysts based on quaternary am-
monium iodides.[6] These reagents were used to cata-
lyze the highly enatioselective intramolecular cyclo-
Benzyl esters are important functional groups in me-
etherification of ketophenols. After that, Ishihara[7]
ACHTUNGTRENNUNG
dicinal and natural organic compounds.[1] Meanwhile, and Wan,[8] respectively applied such a tetrabutylam-
they also act as the essential protecting groups in monium iodide catalyst to the oxidative esterification
amino acids and their derivatives.[2] Benzyl esters of a-C H bonds of carbonyl and ether substrates.
have commonly been prepared by esterification of the Very recently, Nachtsheim and co-workers reported
corresponding benzyl alcohols with carboxylic acids the oxidative amination catalyzed by Bu4NI via pre-
over the decades (Scheme 1, equation a).[3] With the activation of acetic acid.[9] These reports revealed that
À
Scheme 1. Different pathways for the synthesis of benzyl esters.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. The coupling reactions between a variety of carbox-
ylic acids and ethylbenzene.[a]
Entry Catalyst (mol%) Oxidant (equiv.)[b] Yield [%][c]
1
2
3
4
5
6
7
8
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
–
Bu4NF (20)
Bu4NCl (20)
Bu4NBr (20)
NaI (20)
TBHP (2)
t-BuOO-t-Bu (2)
H2O2 (2)
DDQ
PhIACTHNGURETNNU(G OAc)2
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (1)
TBHP (2)
98
N.R.
N.R.
trace
29
N.R.
trace
trace
trace
trace
N.R.
91
9
10
11
12
13
14
15d)
CuI (20)
Bu4NI (10)
Bu4NI (5)
Bu4NI (20)
Bu4NI (20)
78
31
52
[a]
Reaction conditions: benzoic acid (1 mmol) and ethylben-
zene (20 mmol) at 808C for 8 h unless otherwise noted.
Experiments were performed with pure t-BuOO-t-Bu
and TBHP (75% aqueous solution) or H2O2 (30% in
water).
Yield of isolated product.
Reaction was performed with ethylbenzene (5 mmol) in
EtOAc as solvent.
[b]
[c]
[d]
the carboxylic acids could be coupled with highly re-
À
active C H substrates catalyzed by Bu4NI under oxi-
dative conditions. Herein, we expand the application
of the Bu4NI-catalyzed esterification by using benzyl
À
C H containing substrates (Scheme 1, equation c).
These compounds were demonstrated to be suitable
for the oxidative coupling with a variety of carboxylic
acids including N-Boc amino acids, and gave the de-
sired ester products with good to excellent yields.
Benzoic acid and ethylbenzene were chosen as
model substrates to optimize the conditions of oxida-
tive coupling, and the results are summarized in
Table 1. To our delight, the combination of Bu4NI
[a]
Reaction conditions: carboxylic acid (1 mmol), ethylben-
zene (20 mmol), Bu4NI (20 mol%), TBHP (2 equiv., 75%
aqueous solution), 808C, 8 h.
Reaction time was 10 h.
[b]
[c]
Reaction time was 3 h.
(20 mol%) and tert-butyl hydroperoxide (TBHP, 2 duced yield of 78% was obtained with the use of
equiv.) exhibited excellent catalytic activity and gave 5 mol% Bu4NI (entries 12 and 13). The reaction em-
the desired product 3a with 98% yield (entry 1). The ploying only 1 equiv. of TBHP also gave product 3a
use of some other peroxides or common oxidants in- in dramatically decreased yield (entry 14). In addi-
stead of TBHP decreased the yields dramatically (en- tion, ethylbenzene was used as both substrate and sol-
tries 2–5). Bu4NI is the essential element for the reac- vent in this reaction. The yield dropped to 52% after
tion. No reaction happened without the use of Bu4NI the decreasing the amount of ethylbenzene and using
(entry 6), and only traces of product were detected ethyl acetate as solvent (entry 15).
after the change of anions on the quaternary ammoni-
A wide range of carboxylic acids was then em-
um salts (entries 7–9). Other iodides such as NaI and ployed for oxidative coupling with ethylbenzene
CuI also showed no catalytic activity (entries 10 and under our optimized conditions (Table 2). Various
11). Decreasing the amount of Bu4NI to 10 mol% led benzoic acids with electron-donating and electron-
to slightly decreased yield of 91%, while a further re- withdrawing substituents could be converted to the
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A Metal-Free Oxidative Esterification of the Benzyl C H Bond
Table 3. The coupling reactions between benzoic acid and
Table 4. The coupling reactions between N-Boc amino acids
and benzyl C H substrates.
[a]
hydrocarbons.[a]
À
Entry Amino acid deriv- Substrate 1
Product Yield
[%]
atives
1
2
3
4
5
6
7
8
Boc-Gly
toluene
ethylbenzene 6b
toluene 6c
ethylbenzene 6d
toluene 6e
ethylbenzene 6f
toluene 6g
ethylbenzene 6h
toluene 6i
ethylbenzene 6j
6a
69
85
64
83
80
99
82
67
61
90
l-Boc-Ala
l-Boc-Leu
l-Boc-Phe
l-Boc-Pro
9
10
[a]
Reaction conditions: carboxylic acid (1 mmol), ethylben-
zene (20 mmol), Bu4NI (20 mol%), TBHP (2 equiv., 75%
aqueous solution), 808C, 8 h.
substrates like cumene 1e, which has only one benzyl
C H bond, could also react with benzoic acid to give
the product 4e in 75% yield. The quantitative yield
from the reaction of diphenylmethane 1f might be at-
tributed to the more stable intermediate of the cou-
pling. Meanwhile, the polycyclic substrate tetralin 1g
[a]
À
Reaction conditions: benzoic acid (1 mmol), benzyl C H
substrate (20 mmol), Bu4NI (20 mol%), TBHP (2 equiv.,
75% aqueous solution), 808C, 10 h.
Reaction time was 3 h.
À
[b]
desired products (3b–3i) in good to excellent yields. also only gave mono-ester product 4g with 75% yield.
Remarkably, some ortho-substituted benzoic acids (3h The protection of carboxylic groups on amino acids
and 3i) with steric hindrance also gave the products plays an important role in the synthesis or modifica-
with high yields. 1-Naphthoic acid 2l could give the tion of peptides.[11] The positive results obtained
ester product almost quantitatively, while heterocyclic above encouraged us to investigate this metal-free
carboxylic acids such as a-pycolinic acid 2j and b- catalytic system toward the protection of amino acids.
furoic acid 2k gave the respective products in moder- To our delight, the method was suitable for a series of
ate yields. Some aliphatic carboxylic acids also react- N-Boc-protected amino acids (Table 4). Except phe-
ed smoothly with ethylbenzene to give products 3m– nylalanine, all N-Boc-protected amino acids reacted
3t. Among these samples, the synthesis of 1-phenyl- with ethylbenzene to give the ester product in higher
ethyl 2-(3-benzoylphenyl)propanoate (3o) was an im- yields than those with toluene. It is worth mentioning
portant modification of ketoprofen, a common anti- that the optical rotation measurement and chiral
phlogistic drug.[10] Despite the bulky long chain, some HPLC analysis proved the maintenance of the optical
fatty acids could give the ester products with good activities of the amino acid derivatives after the reac-
yields (3s, 3t). These results demonstrate the univer- tion (see the Supporting Information). Therefore this
sality of this oxidative esterification method.
Subsequently, different substrates with benzylic C
H bonds were tested for this esterification with ben- could not give the similar ester product, and this
zoic acid. As shown in Table 3, toluene reacted with might be attributed to the free amino group which is
benzoic acid to give the product 4a in only moderate unfavorable for the reaction.
method could be an efficient protection method for
amino acids. In addition, non-protected amino acids
À
yield (59%). But for xylenes (1b and 1c) or mesity-
Several control experiments were performed to
lene (1d), nearly quantitative yields were obtained. probe the reaction mechanism (Scheme 2). Firstly, the
This might be due to the more reactive positions competitive esterifications involving toluene and its
À
(benzyl C H bonds) on xylene and mesitylene than deuterated derivative toluene-d8 were performed
those on toluene. Additionally, both xylenes and me- (Scheme 2, equation a). Obvious kinetic isotope ef-
sitylene gave only the mono-ester product with high fects (kH/kD =9/1) was observed, indicating that the
À
selectivity, and no multi-ester was detected. Other cleavage of benzyl C H bond is involved in the rate-
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Scheme 2. Investigation of the reaction mechanism. Reaction conditions: carboxylic acid (1 mmol), benzyl C H substrate
(20 mmol).
Scheme 3. Investigation of the catalytically active species and the reaction intermediate. Reaction conditions: benzoic acid
(1 mmol), ethylbenzene, 1-phenylethanol or a-iodoethylbenzene (20 mmol).
determining step. Secondly, addition of the radical separated in 58% yield. The results indicates that the
scavenger
2,2,6,6-tetramethylpiperidine
N-oxide benzyl radical was involved in the catalytic cycle of
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) this esterification.[12]
decreased the yield of the model reaction (Scheme 2,
The mechanisms of polyvalent iodine-catalyzed
equations b and c). In the reaction using TEMPO, the functionalizations were comprehensively discussed in
oxyamination product 9, which was formed through recent reports. Wan and co-workers suggested that
the trapping of the benzyl radical by TEMPO, was the reaction of Bu4NI with oxidant generates iodine
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A Metal-Free Oxidative Esterification of the Benzyl C H Bond
Scheme 4. Proposed reaction mechanism. Reaction conditions: benzoic acid (1 mmol) and ethylbenzene (20 mmol) at 808C
for 8 h.
which further captures the single electron from the re- proton of benzoic acid to give the benzoate anion and
actant.[8,13] Ishihara and other groups speculated an al- a water molecule. The final coupling between the
ternative mechanism that involves hypoiodite as the benzoate anion and benzyl cation gives the ester
actual oxidant.[7,9,14] Wei and co-workers determined product.
[IO2]À as the catalytically active species by ESI-MS
In conclusion, we have described the direct esterifi-
À
analysis, although they could not rule out the possibil- cation of a benzyl C H bond catalyzed by tetrabutyl-
ity of [IO]À species.[14] Hence, more control experi-
ammonium iodide and TBHP as co-oxidant. This
ments were needed to elucidate the reaction mecha- metal-free catalytic system is suitable for the coupling
nism of this transformation. As shown in Scheme 3, reactions between a wide range of carboxylic acids
replacing Bu4NI with I2 led to no product (Scheme 3, and benzyl substrates. It could be conveniently ap-
equation a). However, the combined using of plied to the O-benzyl protection of amino acids.
Bu4NOH and I2 well catalyzed the same esterification Based on the control experiments, a radical catalytic
in 59% yield (Scheme 3, equation b). This result is cycle was proposed. Further studies to elucidate the
similar to those reported by Ishihara,[6] in which the mechanism and to expand the synthetic scope of this
in situ generated hypoiodite ([IO]À or [IO2]À) plays an reaction are currently in progress.
important role in the reaction process. To find out
whether benzyl alcohol or benzyl iodide was formed
in situ as active intermediate, the two compounds
were applied to the title reaction with benzoic acid re-
spectively (Scheme 3, equations c and d). No ester
product was obtained in both reactions.
Experimental Section
From the results of the control experiments and the
studies reported by Kita[15] and Shi,[4h] we speculate
that, during the reaction, the benzyl radical is oxi-
dized by hypoiodite to generate the benzyl cation,
leading to subsequent reaction with carboxylic acid.
General Esterification of Carboxylic Acids with
Benzyl C H Substrates
À
A reaction vessel was charged with tetrabutylammonium
iodide (74 mg, 0.2 mmol, 20 mol%), carboxylic acid
À
A plausible reaction mechanism was proposed as (1 mmol). After the addition of the benzyl C H substrate
(20 mmol, 20 equiv.) and TBHP (70% wt% in water,
300 mL, 2 mmol, 2 equiv.), the reaction mixture was stirred
at 808C in the air until fully conversion by TLC observation.
After recovering excess benzylic component by distillation,
the reaction was quenched by addition of a saturated solu-
tion of sodium thiosulfate. The mixture was extracted with
ethyl acetate (3ꢂ5 mL), the combined organic phases were
dried over Na2SO4 and the solvent was evaporated under
vacuum. The crude residue was purified by column chroma-
tography (silica gel, petroleum ether:ethyl acetate, 20:1 v/v)
shown in Scheme 4. Initially, Bu4NI is oxidized by
TBHP to form the {[Bu4N]+ [IO]À} or {[Bu4N]+ [IO2]À}
species, which is going to induce the homolysis of
À
a benzyl C H bond to give a benzyl radical. This is
the rate-determining step in the whole reaction. The
single electron of hydrogen is captured by hypoiodite
which is subsequently reduced to Bu4NI. The benzyl
radical is liable to be oxidized by the hypoiodite spe-
cies to form the benzyl cation. In this redox process,
the excess oxygen atom of hypoiodite captures the to afford the respective product.
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Acknowledgements
Angew. Chem. 2009, 121, 3875–3878; Angew. Chem.
Int. Ed. 2009, 48, 3817–3820; i) A. Gunay, K. H. Theo-
pold, Chem. Rev. 2010, 110, 1060–1081; j) J. Wencel-
Delord, T. Droge, F. Liu, F. Glorius, Chem. Soc. Rev.
2011, 40, 4740–4761.
This work was financially supported by the National Science
Foundation of China (Nos. 21021001, 20972104), the Pro-
gram for Changjiang Scholars and Innovative Research
Team in University, the Key Project of Chinese Ministry of
Education, and the Scientific Fund of Sichuan Province for
Outstanding Young Scientists. We also thank the Sichuan
University Analytical and Testing Center for NMR spectro-
scopic analysis.
À
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